Association of the expression of 5‑FU biomarkers with aging and prognosis in elderly patients with lung cancer treated with S‑1 adjuvant chemotherapy: Follow‑up results of the Setouchi Lung Cancer Group Study 1201

Soh,Junichi; Yamamoto,Hiromasa; Okumura,Norihito; Suzuki,Hiroyuki; Nakata,Masao; Fujiwara,Toshiya; Gemba,Kenicehi; Sano,Isao; Fujinaga,Takuji; Kataoka,Masafumi; Terasaki,Yasuhiro; Fujimoto,Nobukazu; Kataoka,Kazuhiko; Kosaka,Shinji; Yamashita,Motohiro; Inokawa,Hidetoshi; Inoue,Masaaki; Nakamura,Hiroshige; Yamashita,Yoshinori; Takahashi,Yuta; Torigoe,Hidejiro; Sato,Hiroki; Tomida,Shuta; Hotta,Katsuyuki; Yoshioka,Hiroshige; Morita,Satoshi; Matsuo,Keitaro; Sakamoto,Junichi; Date,Hiroshi; Toyooka,Shinichi

doi:10.3892/mco.2025.2874

Association of the expression of 5‑FU biomarkers with aging and prognosis in elderly patients with lung cancer treated with S‑1 adjuvant chemotherapy: Follow‑up results of the Setouchi Lung Cancer Group Study 1201

Authors:
- Junichi Soh
- Hiromasa Yamamoto
- Norihito Okumura
- Hiroyuki Suzuki
- Masao Nakata
- Toshiya Fujiwara
- Kenicehi Gemba
- Isao Sano
- Takuji Fujinaga
- Masafumi Kataoka
- Yasuhiro Terasaki
- Nobukazu Fujimoto
- Kazuhiko Kataoka
- Shinji Kosaka
- Motohiro Yamashita
- Hidetoshi Inokawa
- Masaaki Inoue
- Hiroshige Nakamura
- Yoshinori Yamashita
- Yuta Takahashi
- Hidejiro Torigoe
- Hiroki Sato
- Shuta Tomida
- Katsuyuki Hotta
- Hiroshige Yoshioka
- Satoshi Morita
- Keitaro Matsuo
- Junichi Sakamoto
- Hiroshi Date
- Shinichi Toyooka
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Affiliations: Department of Thoracic Surgery, Okayama University Hospital, Okayama 700‑8558, Japan, Department of Thoracic Surgery, Kurashiki Central Hospital, Kurashiki, Okayama 710‑8602, Japan, Department of Chest Surgery, Fukushima Medical University Hospital, Fukushima 960‑1295, Japan, Department of General Thoracic Surgery, Kawasaki Medical School Hospital, Kurashiki, Okayama 701‑0192, Japan, Department of Thoracic Surgery, Hiroshima City Hiroshima Citizens Hospital, Hiroshima 730‑8518, Japan, Department of Respiratory Medicine, Chugoku Central Hospital, Fukuyama, Hiroshima 720‑0001, Japan, Department of Respiratory Surgery, Japanese Red Cross Nagasaki Genbaku Hospital, Nagasaki 852‑8511, Japan, Department of General Thoracic Surgery, National Hospital Organization Nagara Medical Center, Gifu 502‑8558, Japan, Department of Surgery and Respiratory Center, Okayama Saiseikai General Hospital, Okayama 700‑8511, Japan, Department of Respiratory Surgery, Saga Medical Center Koseikan, Saga 840‑8571, Japan, Department of Medical Oncology and Respiratory Medicine, Okayama Rosai Hospital, Okayama 702‑8055, Japan, Department of Thoracic Surgery, National Hospital Organization Iwakuni Clinical Center, Iwakuni, Yamaguchi 740‑8510, Japan, Department of Thoracic Surgery, Shimane Prefectural Central Hospital, Izumo, Shimane 693‑8555, Japan, Department of Thoracic Surgery, National Hospital Organization Shikoku Cancer Center, Matsuyama, Ehime 791‑0280, Japan, Department of Thoracic Surgery, National Hospital Organization Yamaguchi‑Ube Medical Center, Ube, Yamaguchi 755‑0241, Japan, Department of Thoracic Surgery, Shimonoseki City Hospital, Shimonoseki, Yamaguchi 750‑8520, Japan, Division of General Thoracic Surgery, Tottori University Hospital, Yonago, Tottori 683‑8504, Japan, Department of Thoracic Surgery, National Hospital Organization Kure Medical Center and Chugoku Cancer Center, Kure, Hiroshima 737‑0023, Japan, Center for Comprehensive Genomic Medicine, Okayama University Hospital, Okayama 700‑8558, Japan, Center for Innovative Clinical Medicine, Okayama University Hospital, Okayama 700‑8558, Japan, Department of Thoracic Oncology, Kansai Medical University Hospital, Hirakata, Osaka 573‑1191, Japan, Department of Biomedical Statistics and Bioinformatics, Kyoto University Graduate School of Medicine, Kyoto 606‑8507, Japan, Division of Cancer Epidemiology and Prevention, Aichi Cancer Center Research Institute, Nagoya, Aichi 464‑8681, Japan, Tokai Central Hospital, Kakamigahara, Gifu 504‑8601, Japan, Department of Thoracic Surgery, Kyoto University Hospital, Kyoto 606‑8507, Japan
Published online on: July 3, 2025 https://doi.org/10.3892/mco.2025.2874
Article Number: 79
Copyright: © Soh et al. This is an open access article distributed under the terms of Creative Commons Attribution License.

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Abstract

Managing elderly patients presents several challenges because of age‑related declines; however, age should not be the sole determinant for adjuvant treatment decisions in patients with non‑small cell lung cancer (NSCLC). Moreover, age may affect the expression of 5‑fluorouracil (5‑FU) biomarkers. The present study assessed: i) The effect of age on the expression levels of 5‑FU biomarkers by analyzing a public database; and ii) the ability of these biomarkers to predict clinical outcomes in elderly patients with NSCLC who underwent complete resection in the Setouchi Lung Cancer Group Study 1201 (SCLG1201) followed by S‑1 adjuvant chemotherapy. Changes in gene expression levels across age groups were assessed by analyzing The Cancer Genome Atlas (TCGA) database. The expression of 5‑FU biomarkers, including thymidylate synthase (TS), dihydropyrimidine dehydrogenase (DPD), orotate phosphoribosyltransferase, epidermal growth factor receptor (EGFR) and excision repair cross‑complementation group 1 (ERCC1), were assessed via quantitative reverse‑transcription PCR assays in 89 elderly patients (≥75 years) with NSCLC who received adjuvant chemotherapy with oral fluoropyrimidine prodrug S‑1 in the SLCG1201 trial. TCGA database analysis (n=955) showed that TS expression decreased significantly with aging, especially in the age group ≥75. In the SCLG1201 trial, univariate analysis revealed that EGFR upregulation and TS downregulation were correlated with favorable recurrence‑free survival (RFS) and overall survival (OS), respectively. Multivariate analysis demonstrated that pathological stage was an independent prognostic factor for both RFS and OS. EGFR mutations were associated with upregulation of DPD and EGFR, and downregulation of TS and ERCC1. In conclusion, although pathological stage is an independent prognostic factor for survival, EGFR upregulation and TS downregulation may be a greater predictor of clinical outcomes in elderly patients with NSCLC treated with S‑1 adjuvant chemotherapy. The age‑related decrease in TS expression supports the potential benefit of 5‑FU therapies in elderly patients. Nonetheless, further research is warranted to validate these results.

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1	Jemal A, Siegel R, Ward E, Hao Y, Xu J and Thun MJ: Cancer statistics, 2009. CA Cancer J Clin. 59:225–249. 2009.PubMed/NCBI View Article : Google Scholar
2	Pallis AG, Gridelli C, Wedding U, Faivre-Finn C, Veronesi G, Jaklitsch M, Luciani A and O'Brien M: Management of elderly patients with NSCLC; updated expert's opinion paper: EORTC elderly task force, lung cancer group and international society for geriatric oncology. Ann Oncol. 25:1270–1283. 2014.PubMed/NCBI View Article : Google Scholar
3	Shirasaka T, Shimamato Y, Ohshimo H, Yamaguchi M, Kato T, Yonekura K and Fukushima M: Development of a novel form of an oral 5-fluorouracil derivative (S-1) directed to the potentiation of the tumor selective cytotoxicity of 5-fluorouracil by two biochemical modulators. Anticancer Drugs. 7:548–557. 1996.PubMed/NCBI View Article : Google Scholar
4	Nishiyama O, Taniguchi H, Kondoh Y, Takada K, Baba K, Saito H, Sugino Y, Yamamoto M, Ogasawara T, Kondo M, et al: Phase II study of S-1 monotherapy as a first-line treatment for elderly patients with advanced nonsmall-cell lung cancer: The Central Japan lung study group trial 0404. Anticancer Drugs. 22:811–816. 2011.PubMed/NCBI View Article : Google Scholar
5	Shiroyama T, Kijima T, Komuta K, Yamamoto S, Minami S, Ogata Y, Okafuji K, Imamura F, Hirashima T, Tachibana I, et al: Phase II tailored S-1 regimen study of first-line chemotherapy in elderly patients with advanced and recurrent non-small cell lung cancer. Cancer Chemother Pharmacol. 70:783–789. 2012.PubMed/NCBI View Article : Google Scholar
6	Goto H, Okano Y, Machida H, Hatakeyama N, Ogushi F, Haku T, Kanematsu T, Urata T, Kakiuchi S, Hanibuchi M, et al: Phase II study of tailored S-1 monotherapy with a 1-week interval after a 2-week dosing period in elderly patients with advanced non-small cell lung cancer. Respir Investig. 56:80–86. 2018.PubMed/NCBI View Article : Google Scholar
7	Yamamoto H, Soh J, Okumura N, Suzuki H, Nakata M, Fujiwara T, Gemba K, Sano I, Fujinaga T, Kataoka M, et al: Randomized phase II study of daily versus alternate-day administrations of S-1 for the elderly patients with completely resected pathological stage IA (tumor diameter >2 cm)-IIIA of non-small cell lung cancer: Setouchi lung cancer group study 1201. PLoS One. 18(e0285273)2023.PubMed/NCBI View Article : Google Scholar
8	Rustum YM, Harstrick A, Cao S, Vanhoefer U, Yin MB, Wilke H and Seeber S: Thymidylate synthase inhibitors in cancer therapy: Direct and indirect inhibitors. J Clin Oncol. 15:389–400. 1997.PubMed/NCBI View Article : Google Scholar
9	Peters GJ, Laurensse E, Leyva A, Lankelma J and Pinedo HM: Sensitivity of human, murine, and rat cells to 5-fluorouracil and 5'-deoxy-5-fluorouridine in relation to drug-metabolizing enzymes. Cancer Res. 46:20–28. 1986.PubMed/NCBI
10	Peters GJ, van Groeningen CJ, Laurensse EJ and Pinedo HM: A comparison of 5-fluorouracil metabolism in human colorectal cancer and colon mucosa. Cancer. 68:1903–1909. 1991.PubMed/NCBI View Article : Google Scholar
11	Beck A, Etienne MC, Chéradame S, Fischel JL, Formento P, Renée N and Milano G: A role for dihydropyrimidine dehydrogenase and thymidylate synthase in tumour sensitivity to fluorouracil. Eur J Cancer. 30A:1517–1522. 1994.PubMed/NCBI View Article : Google Scholar
12	Suehisa H, Toyooka S, Hotta K, Uchida A, Soh J, Fujiwara Y, Matsuo K, Ouchida M, Takata M, Kiura K and Date H: Epidermal growth factor receptor mutation status and adjuvant chemotherapy with uracil-tegafur for adenocarcinoma of the lung. J Clin Oncol. 25:3952–3957. 2007.PubMed/NCBI View Article : Google Scholar
13	Tsutani Y, Ito M, Shimada Y, Ito H, Ikeda N, Nakayama H and Okada M: The impact of epidermal growth factor receptor mutation status on adjuvant chemotherapy for patients with high-risk stage I lung adenocarcinoma. J Thorac Cardiovasc Surg. 164:1306–1315.e4. 2022.PubMed/NCBI View Article : Google Scholar
14	Wei J, Zou Z, Qian X, Ding Y, Xie L, Sanchez JJ, Zhao Y, Feng J, Ling Y, Liu Y, et al: ERCC1 mRNA levels and survival of advanced gastric cancer patients treated with a modified FOLFOX regimen. Br J Cancer. 98:1398–1402. 2008.PubMed/NCBI View Article : Google Scholar
15	Shigematsu H, Lin L, Takahashi T, Nomura M, Suzuki M, Wistuba II, Fong KM, Lee H, Toyooka S, Shimizu N, et al: Clinical and biological features associated with epidermal growth factor receptor gene mutations in lung cancers. J Natl Cancer Inst. 97:339–346. 2005.PubMed/NCBI View Article : Google Scholar
16	Tokumo M, Toyooka S, Kiura K, Shigematsu H, Tomii K, Aoe M, Ichimura K, Tsuda T, Yano M, Tsukuda K, et al: The relationship between epidermal growth factor receptor mutations and clinicopathologic features in non-small cell lung cancers. Clin Cancer Res. 11:1167–1173. 2005.PubMed/NCBI
17	Soh J, Toyooka S, Matsuo K, Yamamoto H, Wistuba II, Lam S, Fong KM, Gazdar AF and Miyoshi S: Ethnicity affects EGFR and KRAS gene alterations of lung adenocarcinoma. Oncol Lett. 10:1775–1782. 2015.PubMed/NCBI View Article : Google Scholar
18	Viñuela A, Snoek LB, Riksen JA and Kammenga JE: Genome-wide gene expression regulation as a function of genotype and age in C. elegans. Genome Res. 20:929–937. 2010.PubMed/NCBI View Article : Google Scholar
19	Li Z, Wright FA and Royland J: Age-dependent variability in gene expression in male Fischer 344 rat retina. Toxicol Sci. 107:281–292. 2009.PubMed/NCBI View Article : Google Scholar
20	Yang J, Huang T, Petralia F, Long Q, Zhang B, Argmann C, Zhao Y, Mobbs CV, Schadt EE, Zhu J, et al: Synchronized age-related gene expression changes across multiple tissues in human and the link to complex diseases. Sci Rep. 5(15145)2015.PubMed/NCBI View Article : Google Scholar
21	Peters MJ, Joehanes R, Pilling LC, Schurmann C, Conneely KN, Powell J, Reinmaa E, Sutphin GL, Zhernakova A, Schramm K, et al: The transcriptional landscape of age in human peripheral blood. Nat Commun. 6(8570)2015.PubMed/NCBI View Article : Google Scholar
22	Jang H, Mason JB and Choi SW: Genetic and epigenetic interactions between folate and aging in carcinogenesis. J Nutr. 135 (Suppl):2967S–2971S. 2005.PubMed/NCBI View Article : Google Scholar
23	Soh J, Okumura N, Lockwood WW, Yamamoto H, Shigematsu H, Zhang W, Chari R, Shames DS, Tang X, MacAulay C, et al: Oncogene mutations, copy number gains and mutant allele specific imbalance (MASI) frequently occur together in tumor cells. PLoS One. 4(e7464)2009.PubMed/NCBI View Article : Google Scholar
24	Liang Z, Zhang J, Zeng X, Gao J, Wu S and Liu T: Relationship between EGFR expression, copy number and mutation in lung adenocarcinomas. BMC Cancer. 10(376)2010.PubMed/NCBI View Article : Google Scholar
25	Pinter F, Papay J, Almasi A, Sapi Z, Szabo E, Kanya M, Tamasi A, Jori B, Varkondi E, Moldvay J, et al: Epidermal growth factor receptor (EGFR) high gene copy number and activating mutations in lung adenocarcinomas are not consistently accompanied by positivity for EGFR protein by standard immunohistochemistry. J Mol Diagn. 10:160–168. 2008.PubMed/NCBI View Article : Google Scholar
26	Mochinaga K, Tsuchiya T, Nagasaki T, Arai J, Tominaga T, Yamasaki N, Matsumoto K, Miyazaki T, Nanashima A, Hayashi T, et al: High expression of dihydropyrimidine dehydrogenase in lung adenocarcinoma is associated with mutations in epidermal growth factor receptor: Implications for the treatment of non-small-cell lung cancer using 5-fluorouracil. Clin Lung Cancer. 15:136–144.e4. 2014.PubMed/NCBI View Article : Google Scholar
27	Tominaga T, Tsuchiya T, Mochinaga K, Arai J, Yamasaki N, Matsumoto K, Miyazaki T, Nagasaki T, Nanashima A, Tsukamoto K and Nagayasu T: Epidermal growth factor signals regulate dihydropyrimidine dehydrogenase expression in EGFR-mutated non-small-cell lung cancer. BMC Cancer. 16(354)2016.PubMed/NCBI View Article : Google Scholar
28	Zhang L, Pradhan B, Guo L, Meng F and Zhong D: EGFR exon 19-deletion aberrantly regulate ERCC1 expression that may partly impaired DNA damage repair ability in non-small cell lung cancer. Thorac Cancer. 11:277–285. 2020.PubMed/NCBI View Article : Google Scholar
29	Lin CS, Liu TC, Lai JC, Yang SF and Tsao TC: Evaluating the prognostic value of ERCC1 and thymidylate synthase expression and the epidermal growth factor receptor mutation status in adenocarcinoma non-small-cell lung cancer. Int J Med Sci. 14:1410–1417. 2017.PubMed/NCBI View Article : Google Scholar
30	Gandara DR, Grimminger P, Mack PC, Lara PN Jr, Li T, Danenberg PV and Danenberg KD: Association of epidermal growth factor receptor activating mutations with low ERCC1 gene expression in non-small cell lung cancer. J Thorac Oncol. 5:1933–1938. 2010.PubMed/NCBI View Article : Google Scholar
31	Ren S, Chen X, Kuang P, Zheng L, Su C, Li J, Li B, Wang Y, Liu L, Hu Q, et al: Association of EGFR mutation or ALK rearrangement with expression of DNA repair and synthesis genes in never-smoker women with pulmonary adenocarcinoma. Cancer. 118:5588–5594. 2012.PubMed/NCBI View Article : Google Scholar
32	Nakamura H, Kawasaki N, Taguchi M and Kabasawa K: Survival impact of epidermal growth factor receptor overexpression in patients with non-small cell lung cancer: A meta-analysis. Thorax. 61:140–145. 2006.PubMed/NCBI View Article : Google Scholar
33	Takeda M, Okamoto I, Hirabayashi N, Kitano M and Nakagawa K: Thymidylate synthase and dihydropyrimidine dehydrogenase expression levels are associated with response to S-1 plus carboplatin in advanced non-small cell lung cancer. Lung Cancer. 73:103–109. 2011.PubMed/NCBI View Article : Google Scholar
34	Honma Y, Togo S, Shimizu K, Tulafu M, Hayashi T, Uekusa T, Tominaga S, Kido K, Fujimoto Y, Nanba Y, et al: Expression of thymidylate synthase predicts clinical outcomes of S-1-based chemotherapy in squamous cell lung cancer. Oncol Lett. 14:3319–3326. 2017.PubMed/NCBI View Article : Google Scholar
35	Liu Q, Yu Z, Xiang Y, Wu N, Wu L, Xu B, Wang L, Yang P, Li Y and Bai L: Prognostic and predictive significance of thymidylate synthase protein expression in non-small cell lung cancer: A systematic review and meta-analysis. Cancer Biomark. 15:65–78. 2015.PubMed/NCBI View Article : Google Scholar
36	Huang CL, Yokomise H, Kobayashi S, Fukushima M, Hitomi S and Wada H: Intratumoral expression of thymidylate synthase and dihydropyrimidine dehydrogenase in non-small cell lung cancer patients treated with 5-FU-based chemotherapy. Int J Oncol. 17:47–54. 2000.PubMed/NCBI
37	Nakano J, Huang C, Liu D, Masuya D, Nakashima T, Yokomise H, Ueno M, Wada H and Fukushima M: Evaluations of biomarkers associated with 5-FU sensitivity for non-small-cell lung cancer patients postoperatively treated with UFT. Br J Cancer. 95:607–615. 2006.PubMed/NCBI View Article : Google Scholar
38	Lenz HJ, Leichman CG, Danenberg KD, Danenberg PV, Groshen S, Cohen H, Laine L, Crookes P, Silberman H, Baranda J, et al: Thymidylate synthase mRNA level in adenocarcinoma of the stomach: A predictor for primary tumor response and overall survival. J Clin Oncol. 14:176–182. 1996.PubMed/NCBI View Article : Google Scholar
39	Okabe T, Okamoto I, Tsukioka S, Uchida J, Hatashita E, Yamada Y, Yoshida T, Nishio K, Fukuoka M, Jänne PA and Nakagawa K: Addition of S-1 to the epidermal growth factor receptor inhibitor gefitinib overcomes gefitinib resistance in non-small cell lung cancer cell lines with MET amplification. Clin Cancer Res. 15:907–913. 2009.PubMed/NCBI View Article : Google Scholar
40	Okabe T, Okamoto I, Tsukioka S, Uchida J, Iwasa T, Yoshida T, Hatashita E, Yamada Y, Satoh T, Tamura K, et al: Synergistic antitumor effect of S-1 and the epidermal growth factor receptor inhibitor gefitinib in non-small cell lung cancer cell lines: Role of gefitinib-induced down-regulation of thymidylate synthase. Mol Cancer Ther. 7:599–606. 2008.PubMed/NCBI View Article : Google Scholar
41	Takezawa K, Okamoto I, Tanizaki J, Kuwata K, Yamaguchi H, Fukuoka M, Nishio K and Nakagawa K: Enhanced anticancer effect of the combination of BIBW2992 and thymidylate synthase-targeted agents in non-small cell lung cancer with the T790M mutation of epidermal growth factor receptor. Mol Cancer Ther. 9:1647–1656. 2010.PubMed/NCBI View Article : Google Scholar
42	Sheng M, Wang F, Zhao Y, Li S, Wang X, Shou T, Luo Y and Tang W: Comparison of clinical outcomes of patients with non-small-cell lung cancer harbouring epidermal growth factor receptor exon 19 or exon 21 mutations after tyrosine kinase inhibitors treatment: A meta-analysis. Eur J Clin Pharmacol. 72:1–11. 2016.PubMed/NCBI View Article : Google Scholar
43	Eck MJ and Yun CH: Structural and mechanistic underpinnings of the differential drug sensitivity of EGFR mutations in non-small cell lung cancer. Biochim Biophys Acta. 1804:559–566. 2010.PubMed/NCBI View Article : Google Scholar
44	Carey KD, Garton AJ, Romero MS, Kahler J, Thomson S, Ross S, Park F, Haley JD, Gibson N and Sliwkowski MX: Kinetic analysis of epidermal growth factor receptor somatic mutant proteins shows increased sensitivity to the epidermal growth factor receptor tyrosine kinase inhibitor, erlotinib. Cancer Res. 66:8163–8171. 2006.PubMed/NCBI View Article : Google Scholar
45	Okabe T, Okamoto I, Tamura K, Terashima M, Yoshida T, Satoh T, Takada M, Fukuoka M and Nakagawa K: Differential constitutive activation of the epidermal growth factor receptor in non-small cell lung cancer cells bearing EGFR gene mutation and amplification. Cancer Res. 67:2046–2053. 2007.PubMed/NCBI View Article : Google Scholar
46	Cho J, Chen L, Sangji N, Okabe T, Yonesaka K, Francis JM, Flavin RJ, Johnson W, Kwon J, Yu S, et al: Cetuximab response of lung cancer-derived EGF receptor mutants is associated with asymmetric dimerization. Cancer Res. 73:6770–6779. 2013.PubMed/NCBI View Article : Google Scholar
47	Imai H, Minemura H, Kishikawa T, Yamada Y, Suzuki K, Umeda Y, Wasamoto S, Kasahara N, Ishihara S, Yamaguchi O, et al: Efficacy and safety of S-1 monotherapy in previously treated elderly patients (aged ≥75 years) with non-small cell lung cancer: A retrospective analysis. Thorac Cancer. 11:2867–2876. 2020.PubMed/NCBI View Article : Google Scholar
48	Tsuchiya T, Arai J, Matsumoto K, Miyazaki T, Honda S, Tagawa T, Nakamura A, Taniguchi H, Sano I, Akamine S, et al: Prognostic impact of the ABCC11/MRP8 polymorphism in adjuvant oral chemotherapy with S-1 for non-small cell lung cancer. Chemotherapy. 61:77–86. 2016.PubMed/NCBI View Article : Google Scholar
49	Uemura T, Oguri T, Maeno K, Sone K, Takeuchi A, Fukuda S, Kunii E, Takakuwa O, Kanemitsu Y, Ohkubo H, et al: ABCC11 gene polymorphism as a potential predictive biomarker for an oral 5-fluorouracil derivative drug S-1 treatment in non-small cell lung cancer. Cancer Chemother Pharmacol. 84:1229–1239. 2019.PubMed/NCBI View Article : Google Scholar